Proximal Tubulopathy Research Articles

Clinical and Biochemical Characteristics of Patients with Renal Tubular Acidosis in Southern Part of West Bengal, India: A Retrospective Study.

Purpose of the Study:Reversible proximal tubular dysfunction associated with distal renal tubular acidosis (dRTA) mimics type 3 RTA, a condition classically associated with features of both proximal RTA (pRTA) and dRTA. Proximal tubulopathy has been reported in children with primary dRTA, but the data in adults are lacking.Study Design:In this hospital record-based retrospective study, data from 66 consecutive cases of RTA, between January 2016 to December 2018, were retrieved and analyzed.Results:Mean age of the study population was 25.3 years (range: 3 months to 73 years). Six (9.1%) of them had pRTA, 58 (87.9%) had dRTA, 1 (1.5%) had type 3 RTA, and the remaining 1 (1.5%) had type 4 RTA. Ten patients (17.2%) with dRTA and 3 patients of pRTA (50%) had underlying secondary etiologies. Data on proximal tubular dysfunction were available for 30 patients with dRTA, of whom 1 had isolated dRTA, and the rest 29 patients had accompanying completely reversible proximal tubular dysfunction. Among the 10 cases of secondary dRTA, 6 were not evaluated for proximal tubular dysfunction. Of the remaining 4, 3 had reversible form of proximal tubular abnormality. Fifty-two patients with dRTA came from a population, indigenous to the “Rarh” region of India.Conclusions:Proximal tubular dysfunction often accompanies dRTA; 75% of the children with primary dRTA, at least 29% of adults with primary dRTA, and at least 30% of adults with secondary dRTA manifest such completely reversible form of proximal tubulopathy. “Rarh’ region of India probably is a hotspot for endemic dRTA.

Случай диагностики проксимальной тубулопатии легких цепей у больного с трансплантированной почкой

Light chain proximal tubulopathy (LCPT) is a disease characterised by accumulation of monoclonal immunoglobulins produced by tumour clones of plasma cells or B-lymphocytes in the epithelium of proximal renal tubules. One of LCPT forms is the crystal one, against the background of which epithelium of proximal renal tubules accumulates crystal structures of different sizes and shapes. This work presents an observation of a kidney transplant patient with crystal LCPT. The patient was admitted with azotaemia and underwent renal biopsy in order to establish the diagnosis. Morphological analysis drew attention to necrosis of epithelium of proximal renal tubules. Electron microscopy visualised crystal structures, immunohistochemical analysis of which revealed their monotypy in relation to lambda light chains of immunoglobulins. LCPT was diagnosed based on the comparison of the morphological picture and clinical data.

Monoclonal gammopathy of renal significance: Spectrum of diseases and approach to a case.

The occurrence of kidney diseases associated with a monoclonal gammopathy in the absence of symptomatic multiple myeloma is increasingly recognized. When the kidney is involved, the monoclonal etiology of these diseases results in clinical and laboratory features distinct from those of other disease, necessitating the nomenclature monoclonal gammopathy of renal significance (MGRS). The detection of these monoclonal diseases involving the kidney is important since they are poorly responsive to conventional immunosuppression and instead require clone-directed therapy. The new International Kidney and Monoclonal research group consensus definition of MGRS includes all proliferative conditions of B cells and/or plasma cells. Renal lesions due to monoclonal immunoglobulins are quite capable of progression with resulting end-stage renal disease development. Hence, these lesions require therapeutic intervention even if they do not satisfy myeloma criteria or the presence of any myeloma defining event. The spectrum of renal lesions that can be observed in a case of MGRS is wide and mirrors the list that may be seen in a case of any plasma cell neoplasm. This includes Ig light chain, heavy chain, and heavy and light chain amyloidosis; immunotactoid glomerulonephritis (GN); monoclonal immunoglobulin deposition disease including light chain, heavy chain, or heavy and light chain disease; light chain proximal tubulopathy; crystal-storing histiocytosis; proliferative GN with monoclonal immunoglobulin deposits; C3 glomerulopathy with monoclonal gammopathy and cast nephropathy. The initial approach after histological assessment is based on presence or absence of monoclonal immunoglobulin deposits. If monoclonality is evident, it is important to distinguish between conditions with deposition of intact immunoglobulin molecule or light chains only. The treatment of MGRS is directed at the underlying neoplastic B-cell or plasma cell clones.

Acquired Fanconi Syndrome from Ifosfamide

Fanconi syndrome is a renal proximal tubule defect that causes reabsorption defects of electrolytes. The clinical features of Fanconi syndrome are amino aciduria, proteinuria, hypophosphatemia, metabolic acidosis, and glycosuria. In children, it is usually resulting from a genetic defect, such as cystinosis, galactosemia, tyrosinemia, hereditary fructose intolerance, and Wilson disease [1]. However, in adults, it is usually resulting from medications, toxins, and kidney diseases such as light chain proximal tubulopathy and primary amyloidosis [1]. Ifosfamide is a chemotherapy agent that is well known in the literature to cause Fanconi syndrome. Herein, we present a case of a woman with cervical cancer who developed ifosfamide-induced Fanconi syndrome after her fifth cycle of chemotherapy.

Subclinical proximal tubulopathy in hepatitis B: The roles of nucleot(s)ide analogue treatment and the hepatitis B virus.

BACKGROUNDThe recommended monitoring tools for evaluating nucleot(s)ide analogue renal toxicity, such as estimated glomerular filtration rate (eGFR) and phosphatemia, are late markers of proximal tubulopathy. Multiple early markers are available, but no consensus exists on their use.AIMTo determine the 24 mo prevalence of subclinical proximal tubulopathy (SPT), as defined with early biomarkers, in treated vs untreated hepatitis B virus (HBV)-monoinfected patients.METHODSA prospective, non-randomized, multicenter study of HBV-monoinfected patients with a low number of renal comorbidities was conducted. The patients were separated into three groups: Naïve, starting entecavir (ETV) treatment, or starting tenofovir disoproxil (TDF) treatment. Data on the early markers of SPT, the eGFR and phosphatemia, were collected quarterly. SPT was defined as a maximal tubular reabsorption of phosphate/eGFR below 0.8 mmoL/L and/or uric acid fractional excretion above 10%. The prevalence and cumulative incidence of SPT at month 24 (M24) were calculated. Quantitative data were analyzed using analyses of variance or Kruskal-Wallis tests, whereas chi-squared or Fisher’s exact tests were used to analyze qualitative data. Multivariate analyses were used to adjust for any potential confounding factors.RESULTSOf the 196 patients analyzed, 138 (84 naïve, 28 starting ETV, and 26 starting TDF) had no SPT at inclusion. At M24, the prevalence of SPT was not statistically different between naïve and either treated group (21.1% vs 30.7%, P < 0.42 and 50.0% vs 30.7%, P = 0.32 for ETV and TDF, respectively); no patient had an eGFR lower than 50 mL/min/1.73 m² or phosphatemia less than 0.48 mmoL/L. In the multivariate analysis, no explanatory variables were identified after adjustment. The cumulative incidence of SPT over 24 mo (25.5%, 13.3%, and 52.9% in the naïve, ETV, and TDF groups, respectively) tended to be higher in the TDF group vs the naïve group (hazard ratio: 2.283, P = 0.05). SPT-free survival at M24 was 57.6%, 68.8%, and 23.5% for the naïve, ETV, and TDF groups, respectively. The median survival time without SPT, evaluated only in the TDF group, was 5.9 mo.CONCLUSIONThe prevalence and incidence of SPT was higher in TDF-treated patients compared to naïve patients. SPT in the naïve population suggests that HBV can induce renal tubular toxicity.

Monoclonal gammopathy of renal significance; experience of a tertiary care hospital in India

Introduction: Monoclonal gammopathy of renal significance (MGRS) disorders are indolent B-cell or plasma cell lymphoproliferative neoplasms which do not meet the hematological criteria for malignancy, however they cause renal dysfunction as a result of production of nephrotoxic monoclonal immunoglobulin (MIg). Objectives: To study the clinical presentation, laboratory features, light microscopy and immunofluorescence (IF) characteristics of all cases of MGRS diagnosed at our hospital over a period of five years. Patients and Methods: A record of all renal biopsies performed at our hospital between 2014-2019 was accessed from the database. Out of 1356 kidney biopsies, 68 had evidence of MIg deposition on immunofluorescence. Only six cases met the criteria of MGRS. Histopathological and immunofluorescence characteristics were studied to classify the lesions as per International Kidney and Monoclonal Gammopathy (IKMG) Research Group classification. Results: All six cases presented with deranged renal function. Four had sub-nephrotic and one had nephrotic range proteinuria. MIg was identified in only one case on serum protein electrophoresis and free light chain assay. Using a conjunction of histomorphology of renal lesions, special stains and immunofluorescence all six cases of MGRS were categorized as per IKMG classification into monoclonal immunoglobulin deposition disease (two cases), AL amyloidosis, light chain cast nephropathy, proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) and light chain proximal tubulopathy (LCPT). Conclusion: MGRS presents as renal failure and proteinuria. MIg may not be detected on protein electrophoresis due to low-secretion in serum. A kidney biopsy is essential to study the morphology of renal lesions and identify MIg deposition.

Hemolysis induced by Left Ventricular Assist Device is associated with proximal tubulopathy.

Chronic subclinical hemolysis is frequent in patients implanted with Left Ventricular Assist Device (LVAD) and is associated with adverse outcomes. Consequences of LVADs-induced subclinical hemolysis on kidney structure and function is currently unknown. Thirty-three patients implanted with a Heartmate II LVAD (Abbott, Inc, Chicago IL) were retrospectively studied. Hemolysis, Acute Kidney Injury (AKI) and the evolution of estimated Glomerular Filtration Rate were analyzed. Proximal Tubulopathy (PT) groups were defined according to proteinuria, normoglycemic glycosuria, and electrolytic disorders. The Receiver Operating Characteristic (ROC) curve was used to analyze threshold of LDH values associated with PT. Median LDH between PT groups were statistically different, 688 IU/L [642-703] and 356 IU/L [320-494] in the "PT" and "no PT" groups, respectively p = 0.006. To determine PT group, LDH threshold > 600 IU/L was associated with a sensitivity of 85.7% (95% CI, 42.1-99.6) and a specificity of 84.6% (95% CI, 65.1-95.6). The ROC's Area Under Curve was 0.83 (95% CI, 0.68-0.98). In the "PT" group, patients had 4.2 [2.5-5.0] AKI episodes per year of exposure, versus 1.6 [0.4-3.7] in the "no PT" group, p = 0.03. A higher occurrence of AKI was associated with subsequent development of Chronic Kidney Disease (CKD) (p = 0.02) and death (p = 0.05). LVADs-induced subclinical hemolysis is associated with proximal tubular functional alterations, which in turn contribute to the occurrence of AKI and subsequent CKD. Owing to renal toxicity of hemolysis, measures to reduce subclinical hemolysis intensity as canula position or pump parameters should be systematically considered, as well as specific nephroprotective therapies.

Two new missense mutations in the protein interaction ASH domain of OCRL1 identified in patients with Lowe syndrome.

The oculocerebrorenal syndrome of Lowe is a rare X-linked disease characterized by congenital cataracts, proximal renal tubulopathy, muscular hypotonia and mental impairment. This disease is caused by mutations in the OCRL gene encoding membrane bound inositol polyphosphate 5-phosphatase OCRL1. Here, we examined the OCRL gene of two Lowe syndrome patients and report two new missense mutations that affect the ASH domain involved in protein-protein interactions. Genomic DNA was extracted from peripheral blood of two non-related patients and their relatives. Exons and flanking intronic regions of OCRL were analyzed by direct sequencing. Several bioinformatics tools were used to assess the pathogenicity of the variants. The three-dimensional structure of wild-type and mutant ASH domains was modeled using the online server SWISS-MODEL. Clinical features suggesting the diagnosis of Lowe syndrome were observed in both patients. Genetic analysis revealed two novel missense variants, c.1907T>A (p.V636E) and c.1979A>C (p.H660P) in exon 18 of the OCRL gene confirming the clinical diagnosis in both cases. Variant c.1907T>A (p.V636E) was inherited from the patient's mother, while variant c.1979A>C (p.H660P) seems to have originated de novo. Analysis with bioinformatics tools indicated that both variants are pathogenic. Both amino acid changes affect the structure of the OCRL1 ASH domain. In conclusion, the identification of two novel missense mutations located in the OCRL1 ASH domain may shed more light on the functional importance of this domain. We suggest that p.V636E and p.H660P cause Lowe syndrome by disrupting the interaction of OCRL1 with other proteins or by impairing protein stability.

Design and methods of the prevalence and pharmacogenomics of tenofovir nephrotoxicity in HIV-positive adults in south-western Nigeria study

BackgroundIndividuals of African descent are at higher risk of developing kidney disease than their European counterparts, and HIV infection is associated with increased risk of nephropathy. Despite a safe renal profile in the clinical trials, long-term use of tenofovir disoproxil fumarate (TDF) has been associated with proximal renal tubulopathy although the underlying mechanisms remain undetermined. We aim to establish the prevalence of and risk factors for TDF-induced kidney tubular dysfunction (KTD) among HIV-I and II individuals treated with TDF in south-west Nigeria. Association between TDF-induced KTD and genetic polymorphisms in renal drug transporter genes and the APOL1 (Apolipoprotein L1) gene will be examined.MethodsThis study has two phases. An initial cross-sectional study will screen 3000 individuals attending the HIV clinics in south-west Nigeria for KTD to determine the prevalence and risk factors. This will be followed by a case-control study of 400 KTD cases and 400 matched controls to evaluate single nucleotide polymorphism (SNP) associations. Data on socio-demographics, risk factors for kidney dysfunction and HIV history will be collected by questionnaire. Blood and urine samples for measurements of severity of HIV disease (CD4 count, viral load) and renal function (creatinine, eGFR, phosphate, uric acid, glucose) will also be collected. Utility of urinary retinol binding protein (RBP) and N-acetyl-beta-D-glucosaminidase (NAG) levels as surrogate markers of KTD will be evaluated. Genomic DNA will be extracted from whole blood and SNP analyses performed using the rhAMP SNP genotyping assays. Statistical analysis including univariate and multivariate logistic regression analyses will be performed to identify factors associated with KTD.DiscussionIn spite of TDF being the most commonly used antiretroviral agent and a key component of many HIV treatment regimens, it has potential detrimental effects on the kidneys. This study will establish the burden and risk factors for TDF-induced KTD in Nigerians, and explore associations between KTD and polymorphisms in renal transporter genes as well as APOL1 risk variants. This study may potentially engender an approach for prevention as well as stemming the burden of CKD in sub-Saharan Africa where GDP per capita is low and budgetary allocation for health is inadequate.

Peculiarities of acid-releasing renal function of rats in the dynamics of experimental diabetes mellitus with underlying pharmacological blockade of renin-angiotensin-aldosterone system

Annotation. The aim of the study was to explore the peculiarities of acid-releasing renal function of rats in the dynamics of alloxan-induced experimental diabetes mellitus (EDM) with underlying pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS). The experiments were carried out on 78 white non-linear mature male rats with 11-, 26- and 46-day long alloxan-induced EDM with underlying pharmacological blockade of RAAS by administration of captopril. The study of acid-releasing renal function was provided under the condition of water 2-hour diuresis by changes in urine pH, excretion of titrated acids (TA), ammonia and active hydrogen ions with calculations of their excretion and ratio indices, standardization per 100 μl of glomerular filtrate (GF) volume. It was found that after administration of captopril to rats with 11-day long EDM urine pH, excretion of active hydrogen ions, ammonia excretion increased, TA excretion reduced, including it standardized by the volume of GF, as well as standardized excretion of ammonium compounds. After captopril administration to the animals with a 26-day long EDM, urine pH and TA excretion raised, and the excretion of ammonium and hydrogen ions decreased, still exceeding the control values. Standardized by GF, these indices changed similarly. After pharmacological blockade of RAAS on the 46th day of EDM urine pH, TA excretion, including it standardized by GF, excretion of hydrogen ions enhanced. Excretion of ammonium compounds, including it standardized by GF, and standardized excretion of hydrogen ions declined as compared with control parameters. Thus, the intensification of acid-release at the early stages of EDM is systemic by character and develops due to glomerular hyperfiltration, overload of the nephron with acidic products of metabolism and accompanied by structural intactness of the tubular apparatus of the kidneys. Prolonged glomerular hyperfiltration, probably, is the initiating damaging factor for the tubular apparatus of the diabetic kidney, which in 26-day long EDM is accompanied by the inability of enzyme systems of tubular epithelial cells of proximal tubules, mostly, to provide adequate ammoniogenesis, despite the high efficacy of renal transport mechanisms of acid-release. Proximal tubulopathy on the background of augmented aciduria in animals with 46-day long EDM causes relative functional insufficiency of the distal tubular apparatus.

S2580 Plasmapharesis for Hyperbilirubinemia: A Bridge to Transplant

INTRODUCTION: Plasma exchange (PE) has been used to successfully treat hyperbilirubinemia in conditions such as primary biliary cholangitis. However, it is not routinely used to prevent worsening renal function due to bile cast nephropathy, as a bridge to liver transplant. We present a case of using PE to treat severe hyperbilirubinemia in a patient with acute on chronic liver failure prior to orthotopic liver transplantation (OLT). CASE DESCRIPTION/METHODS: This is a 62 year old woman with a past medical of NASH cirrhosis, esophageal varices, hepatic encephalopathy, and factor V leiden deficiency who presented to our institution for management of worsening liver function. On admission, her total bilirubin was 29.3mg/dl (baseline was around 5mg/dl), direct bilirubin 18mg/dl and MELD was 21. Hemolysis workup was negative. She had completed a course of azithromycin for pneumonia, raising concern for drug induced liver injury. MRI abdomen revealed portal vein thrombosis, splenomegaly, portal enteropathy, ascites and no biliary ductal dilation. Her course was complicated by worsening bilirubin up to 70mg/dl and subsequent worsening kidney function with a creatinine of 3.90 mg/dl concerning for cholestatic nephrosis. She was transferred to the intensive care unit where she received two sessions of PE. After PE her bilirubin improved to 40 mg/dl, her creatinine improved to 1.39 mg/dl and urine output improved. Patient was re-MELDed at 40. She successfully underwent OLT ten days after her last PE session. Post-OLT, her bilirubin and creatinine normalized. DISCUSSION: While we are transplanting at higher MELD scores, we see patients with severe hyperbilirubinemia, which can cause significant complications, including bile cast nephropathy. Cholemic nephrosis can cause renal injury from proximal tubulopathy to intrarenal bile cast formation. PE has been used to successfully treat hyperbilirubinemia in few cases of fulminant hepatic failure not amendable to OLT in an attempt to allow hepatocyte recovery and regeneration. However, it is not routinely used to treat hyperbilirubinemia in liver failure as a bridge to transplant. Preserving renal function is important for a successful post-transplant course. Our case is one of the few cases in the literature where PE was used as a bridge prior to OLT in patients with hyperbilirubinemia in the setting of acute on chronic liver failure. Hence we conclude that PE can be considered to treat hyperbilirubinemia to prevent renal failure as a bridge to transplant.

Kidney and Metabolic Phenotypes in Glycogen Storage Disease Type-I Patients.

Patients and Methods: A retrospective chart review of 32 GSD- I patients, followed at the American University of Beirut Medical Center, between 2007 and 2018 was conducted. Diagnosis was confirmed by enzymatic and/or genetic studies. Clinical presentation, growth, and kidney outcome were assessed. All patients were evaluated for body mass index, blood parameters of metabolic control including uric acid, alanine, lactic acid, and triglycerides in blood. Kidney evaluation included creatinine clearance, microalbuminuria, citraturia, and calciuria as well as urine microalbumin/creatinine ratio.Results: Almost one third of GSD-I patients developed microalbuminuria. This was detected below 7 months of age in 36% of patients who required early treatment with ACEI with significant reduction in albuminuria. Kidney stones were present in 6% and were associated with hypercalciuria and hypocitraturia. Poor metabolic control reflected by hyperuricemia, lactic acidosis, and hyperalaninemia were noted only in patients who developed microalbuminuria.Conclusion: Glomerular injury may appear in early infancy in poorly controlled patients. Adequate metabolic control and ACEI therapy may improve kidney outcome in GSD I patients. Plasma alanine appears to be a promising and reliable marker reflecting metabolic control in GSD-I patients.

Renal proximal tubulopathy in an HIV-infected patient treated with tenofovir alafenamide and gentamicin: a case report

BackgroundThe nucleotide reverse transcriptase inhibitor Tenofovir Alafenamide (TAF) is a novel pro-drug of tenofovir (TFV) and possesses a superior renal safety profile compared with tenofovir disoproxil fumerate (TDF). Due to unique pharmacokinetic characteristics, treatment with TAF is not associated with significant renal proximal tubular accumulation of TFV. TAF is associated with a lower risk of acute kidney injury, chronic kidney disease, proteinuria and renal proximal tubular dysfunction than treatment with TDF. No cases of Fanconi syndrome have been reported in clinical trials of TAF. It is unknown whether treatment with TAF can lead to accumulation of TFV in proximal tubular cells and cause nephrotoxicity under certain clinical circumstances.Case presentationHere we report the case of a patient on stable TAF-based antiretroviral therapy with for HIV-1 infection who developed proximal tubulopathy when treated with gentamicin for febrile neutropenia in the context of relapsed Hodgkin lymphoma. Eighteen days after commencing chemotherapy for relapsed Hodgkin lymphoma the patient presented to hospital with fevers, hypotension and neutropenia. The patient was commenced on piperacillin, tazobactam and gentamicin. Within 24 h the patient developed marked hypokalaemia and hypophosphataemia requiring intravenous replacement therapy. There was proteinuria, glycosuria and evidence of marked urinary electrolyte wasting, consistent with acute proximal tubular dysfunction. Eleven days after the gentamicin was stopped the serum biochemistry normalised. The urinary electrolyte wasting and proteinuria had improved, and the glycosuria had resolved.ConclusionThis is the first case report to describe acute renal proximal tubulopathy in an HIV-infected patient treated with TAF and gentamicin. As the number of patients prescribed TAF outside the clinical trial setting increases, so too does the potential for previously unreported drug interactions and adverse events. Clinicians need to be aware of potential unreported adverse drug reactions as the use of TAF becomes increasingly common in clinical practice.

Advanced Oxidation Protein Products Contribute to Renal Tubulopathy via Perturbation of Renal Fatty Acids.

Renal proximal tubulopathy plays a crucial role in kidney disease, but its molecular mechanism is incompletely understood. Because proximal tubular cells consume a lot of energy during reabsorption, the relationship between fatty acids (FAs) and proximal tubulopathy has been attracting attention. The purpose of this study is to investigate the association between change in renal FA composition and tubulopathy. Mice with cisplatin-induced nephrotoxicity were used as a model of AKI and 5/6-nephrectomized mice were used as a model of CKD. Renal FA composition in mice was measured by GC-MS. Human tubular epithelial cells (HK-2 cells) were used for in vitro studies. In kidneys of AKI mice, increased stearic acid (C18:0) and decreased palmitic acid (C16:0) were observed, accompanied by increased expression of the long-chain FA elongase Elovl6. Similar results were also obtained in CKD mice. We show that C18:0 has higher tubular toxicity than C16:0 via induction of ER stress. Using adenovirus-expressing Elovl6 or siRNA for Elovl6 in HK-2 cells, we demonstrated that increased Elovl6 expression contributes to tubulopathy via increasing C18:0. Elovl6 knockout suppressed the increased serum creatinine levels, renal ER stress, and inflammation that would usually result after 5/6 nephrectomy. Advanced oxidation protein products (AOPPs), specifically an oxidized albumin, was found to induce Elovl6 via the mTORC1/SREBP1 pathway. AOPPs may contribute to renal tubulopathy via perturbation of renal FAs through induction of Elovl6. The perturbation of renal FAs induced by the AOPPs-Elovl6 system could be a potential target for the treatment of tubulopathy.

Clinicopathologic Assessment of Monoclonal Immunoglobulin-associated Renal Disease in the Kidney Allograft: A Retrospective Study and Review of the Literature.

Monoclonal immunoglobulin (MIg)-associated renal disease (MIgARD) comprises a group of disorders caused by direct deposition of paraproteins in the kidney. Allograft MIgARD is infrequently encountered and poorly characterized. First, we assessed our allograft biopsies diagnosed with MIgARD between 2007 and 2018. The cohort included the following 26 patients: proliferative glomerulonephritis with MIg deposits (PGNMID) (n = 13), AL amyloidosis (n = 5), light chain deposition disease (n = 5), light chain proximal tubulopathy (n = 2), and light chain cast nephropathy (n = 1). Second, we conducted a literature review to evaluate the rare non-PGNMID entities. We identified 20 studies describing 29 patients that were added to our cohort (total n = 42). Part 1: Patients' median age was 55 years; 31% were women, and 19% were blacks. Twelve patients (46%) lost their grafts at a median of 8 months after diagnosis. Compared to non-PGNMID, PGNMID patients had lower frequency of detectable paraproteins (31% versus 92%, P = 0.004) and hematologic neoplasms (23% versus 77%, P = 0.02). Within PGNMID group, 6 patients changed their apparent immunofluorescence phenotype between monotypic and polytypic, while all 3 patients with hematologic neoplasms had substructure on electron microscopy. Part 2: Whereas light chain cast nephropathy occurred the earliest and had the worst graft survival, AL amyloidosis occurred the latest and had the best graft survival. MIgARD in the kidney allograft is associated with poor prognosis. While posttransplant PGNMID can change its apparent clonality by immunofluorescence supporting oligoclonal immune responses, the presence of deposit substructure is an important indicator of underlying hematologic neoplasm. Non-PGNMID are often associated with hematologic neoplasms and varied prognosis.

Coronavirus disease 2019: acute Fanconi syndrome precedes acute kidney injury.

BackgroundRecent data have shown that severe acute respiratory syndrome coronavirus 2 can infect renal proximal tubular cells via Angiotensin Converting Enzyme 2 (ACE2) . Our objective was to determine whether Fanconi syndrome is a frequent clinical feature in coronavirus disease 2019 (COVID-19) patients.MethodsA retrospective cohort of 42 laboratory-confirmed COVID-19 patients without history of kidney disease hospitalized in University Hospital of Nancy was investigated. Patients were admitted to the intensive care unit (ICU) (n = 28) or the Medical department (n = 14) and were screened at least once for four markers of proximal tubulopathy.ResultsThe mean (standard deviation) follow-up was 19.7 (±12.2) days. Of the patients, 75% (30/40) showed at least two proximal tubule abnormalities (incomplete Fanconi syndrome). The main disorders were proteinuria (88%, n = 35), renal phosphate leak defined by renal phosphate threshold/glomerular filtration rate (TmPi/GFR) <0.77 (55%, n = 22), hyperuricosuria (43%, n = 17) and normoglycaemic glycosuria (30%, n = 12). At the time of the first renal evaluation, ICU patients presented more frequent (96 versus 62%, P = 0.0095) and more severe (844 ± 343 versus 350 ± 221 mg/g, P = 0.0001) proteinuria, and a trend for an increased number of proximal tubule abnormalities (P = 0.038). During follow-up, they presented a lower nadir of serum phosphate [median (interquartile range) 0.68 (0.43–0.76) versus 0.77 (0.66–1.07) mmol/L, P = 0.044] and Acute kidney Injury (AKI) during the hospitalization (P = 0.045). Fanconi syndrome preceded severe AKI KDIGO Stages 2 and 3 in 88% (7/8) of patients. Proximal tubular abnormalities (such as proteinuria, TmPi/GFR and glycosuria in five, two and two patients, respectively) were not detected anymore in recovering patients before hospital discharge.ConclusionIncomplete Fanconi syndrome is highly frequent in COVID-19 patients and precedes AKI or disappears during the recovery phase.

The interesting picture: simultaneous occurrence of myeloma cast nephropathy, light chain deposition disease and light chain proximal tubulopathy in a patient with multiple myeloma.

The interesting picture: simultaneous occurrence of myeloma cast nephropathy, light chain deposition disease and light chain proximal tubulopathy in a patient with multiple myeloma.

P0415MONOCLONAL GAMMOPATHY-RELATED RENAL DISEASES: NEW CLINICAL AND HISTOLOGICAL PATTERNS

Abstract Background and Aims In the last few years new clinical-histopathological forms of paraproteinemia associated kidney disease have emerged: light chain proximal tubulopathies, proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) and C3-glomerulopathy. It is now widely recognized that the pathogenic role of the monoclonal protein depends on the free light chain chemical-physical features, even in the case of “dangerous small B cell clones”. Thus MGRS (monoclonal gammopathy of renal significance) associated disease is now considered a different entity from monoclonal gammopathy of undetermined significance (MGUS). Method We retrospectively evaluated the clinical-histopathological features of the biopsies performed in our Nephrological Unit on patients with MGUS in 2008-2018, in order to re-classify them in accordance with the recent scientific literature. Results Nine patients (7 M/2 F; age 46-77 y) were analyzed: five of them suffering from CKD stage 2, four of them with AKI or rapidly progressive CKD, 7 with proteinuria &amp;gt; 1 g/day, 2 with physiological proteinuria. Bone marrow biopsy: 7 patients with MGUS, 2 with smoldering multiple myeloma. Renal biopsy: 4 glomerulopathies (monoclonal fibrillary glomerulonephritis, cryoglobulinaemic (type I) glomerulonephritis, C3 glomerulonephritis, PGNMID), 5 proximal tubulopathies (2 LCPT with Fanconi syndrome, 1 LCPT without cytoplasmic inclusions and with interstitial inflammatory reaction, 2 LCPT with acute tubular necrosis) Table 1, Table 2, Light microscopy and IF of PGNMID. Conclusion MGRS is responsible for the pathogenesis of new histopathological renal lesions, based on new pathogenetic pathways. The clinical and histological features of the different disease states are dependent on the structure of FLCs. Our retrospective analysis of MGRS biopsies confirms how difficult and complex the diagnostic challenge of monoclonal renal injury really is. The differentiation between MGUS and MGRS is based on renal biopsy and demonstration of monoclonality on kidney tissue even if serum/urine immunofixation is negative. Early biomarkers of the pathogenetic role of monoclonal FLC should be identified both for diagnosis and therapeutical monitoring.

P0307KIDNEY-HEMOPATHY CONSULTATION: A SINGLE-CENTER EXPERIENCE

Abstract Background and Aims Renal involvement in plasma cell dyscrasia has been widely described, including Monoclonal Gammopathy of Renal significance (MGRS). Chronic kidney disease (CKD) in hematological disorders carries major implications for management, prognosis and the potential for progressive renal injury and ESRD. Specific monthly Kidney-Hemopathy Consultation has been created in 2017 in the department of Nephrology. The aimed of this was to describe the clinical, biological and histological characteristics of patients with hematological disorders and CKD. Method From 01/05/2017 to 31/12/2019 adults with hematological disorders and CKD (eGFR&amp;lt;60ml/min and/or proteinuria or hematuria) were prospectively included. Results Fifty-six patients (27 men) were enrolled: Multiple Myeloma (n=30), MGUS (n=11), Lymphoma (n=5), Acute Leukemia (n=4), LMC (n=2), 1 LLC (n=2), Cryoglobulinemia (n=1), Refractory Anemia with Excess blasts (n=1), Bone marrow aplasia (n=1). This nephrology consultation was the first for 22 patients (39%), referred by a hematologist in 38 cases (68%). Renal injury was confirmed after the hematologic diagnosis in 34 patients (61%) and precedes the diagnosis of plasma cell dyscrasia for 8 patients (14%). The median eGFR was 54.1ml/min/1.73m (128-4): CKD stage II (n=16), stage III (n=28), stage IV (n=7) and stage V (n=2). Proteinuria was &amp;gt;0.5g/day for 22 (39.3%) patients including a Bence-Jones proteinuria for 15 patients (27%). Acute Kidney Injury (AKI) was confirmed in 34 patients (63%) and 8 (24%) requiring acute dialysis. Histologic diagnostic of kidney injury was confirmed for 21 patients (38%): 16 kidney biopsies and 5 AL renal amyloidosis confirmed by salivary glands or abdominal fat biopsy. MGRS was confirmed in 34 patients (61%): Cast nephropathy (n=10;29%), AL amyloidosis (n=7;20%); C3 nephropathy (n=3; 9%), Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits (n=3), Light Chain Proximal Tubulopathy (n=3), Randall-type monoclonal immunoglobulin deposition disease (n=2, 6%), 1 Minimal Change Disease (n=1; 3%), Glomerulonephritis with Organized Microtubular Monoclonal Ig Deposits (n=1) and exclusive tumoral renal infiltration (n=1). Associated tumoral infiltration or crystalline podocytopathy was confirmed in 2 and 1 biopsy respectively. Glomerular MGRS was highly suspected for 2 patients, even if no biopsy was performed. MGRS was excluded for 22 patients (39%): AKI due to antibiotics or sepsis (n=8; 36%), hypovolemia (n=4; 18%) or hypercalcemia (n=3; 14%); 2 renal artery stenosis due to tyrosine kinase inhibitors (n=2; 9%), nephroangiosclerosis (n=1), lithiasis (n=1), CKD post- nephrectomy CKD (n=1), and immunoallergic nephritis (n=1). Hematological treatment was initiated in 54 patients (96%). All patients with MGRS were treated, whom 17 (50%) completely or partially in the Nephrology department. Proteasome inhibitors, alkylant agents and IMIDs were the main molecule used in first line therapy (56%, 23% and 12% respectively). Eleven patients (20%) had stem cell transplantation. After a median follow up of 16 months (38-0), complete or very good partial hematologic response was obtained in 48 patients (89%); whom 30 with MGRS (88%). Median eGFR was 45ml/min/1.73m (142-4): CKD stage II (n=18), stage III (n=23) and stage IV (n=9). Only 1/3 CKD stade V patient needed chronic replacement therapy. Eight patients died (14%): 4 uncontrolled hematologic disease (50%) and 3 septic complications (38%). Conclusion Very closed collaboration between Nephrology and Hematology Department in our Center contributes to improve early management of patients with hematological disorders associated with CKD, and probably their survey. Hemato-Nephrology is a viable and emergent specialty.

Lambda light chain crystalline proximal tubulopathy with probable light chain cast nephropathy and clonal plasma cell infiltrate – uncommon manifestations of a rare form of multiple myeloma

Light chain proximal tubulopathy (LCPT) is an uncommon renal disease characterized by the accumulation of monoclonal light chains within proximal tubular epithelial cells, with or without crystal formation. We report a rare case of lambda LCPT with crystals. Renal biopsy showed substantial acute tubular injury with unusual cytoplasmic changes affecting proximal tubules. In addition, abnormal tubular casts suggested concomitant light chain cast nephropathy. A clonal plasma cell infiltrate was present in the tubulointerstitial compartment. Immunofluorescence demonstrated strong staining for lambda light chain in tubular epithelial cells. Despite the absence of discernible crystals on light microscopy (LM), they were readily identified when ultrastructural evaluation was undertaken. Crystalline inclusions demonstrated positive immunogold labelling for lambda.